Haloetherification

Haloetherification remains one of the most popular approaches towards tetrahydrofuran skeletons. Yus reported a double iodoetherification reaction promoted by a silver salt, affording l,7-dioxaspiro[4.5]decanes, and an example is shown in the scheme below <06T2264>. Kumar and Singh also reported an iodoetherification pathway to form 2,3-diphenyltetrahydrofurans <06T4018>. A bromoetherification converted 3-butenols into bromotetrahydrofurans <06TL5751>. 

A useful aspect of the mercury(II) hydride method is that it can be directly coupled with the many standard techniques for heteromercuration of alkenes and cyclopropanes. The resulting overall transformation adds a heteroatom and a carbon atom across the carbon-carbon double bond of an alkene or the carbon-carbon single bond of a cyclopropane. This is a difficult transformation to conduct by standard ionic techniques. An alkene thus becomes an equivalent of synthon (12) and a cyclopropane of synthon (13 Scheme 34). Many equivalent transformations (like haloetherification and phenylselenolactoniza-tion) are available to make precursors for tin hydride mediated additions. 

The stereoselectivity of iodolactonization of 2-substituted 4-pentenoic acids (with OH, NHTs or CH2OH group at C-2) by NIS or I2 can be increased in the presence of (PriO)4Ti223. In contrast, the stereochemistry of analogous haloetherification of 2-hydroxymethyl-4-penten-l-ol is reversed by the addition of (Pr O Ti223. 

Alkenylboron compounds cyclopropanations, 9, 181 haloetherification, 9, 182 hydrogenation and epoxidation, 9, 182 metal-catalyzed reactions, 9, 183 metallic reagent additions, 9, 182 via radical addition reactions, 9, 183 5-Alkenylboron compounds, cross-coupling reactions, 9, 208 Alkenyl complexes with cobalt, 7, 51 with copper, 2, 160, 2, 174 with Cp Re(CO) (alkene)3 , 5, 915-916 with dicarbonyl(cyclopentadienyl)hydridoirons, 6, 175 with gold, 2, 255... 

Similar addition mechanisms explain the so-called halolactonization and the related haloetherification (Figure 3.47). With the help of these reactions one can produce halogenated five- and six-membered ring lactones or ethers stereoselectively. Dehalogenation afterward is possible (Figure 1.38). 

Generation of positive-like halogen species in situ has been realized by the oxidation of halide salts with m-chloropeibenzcnc acid (M BA). The procedure can be used for haloetherification and lactoni-zation (equation 28). Oxidation of potassium bromide with MCPBA in the presence of 18-crown-6 (10 mol %) produces m-chlorobenzoylhypobromite, which adds across the double bond to furnish trans-, 2-bromocarboxylates (55 equation 29). ... 

The halocyclization of unsaturated alcohols leading to bicyclic compounds is of interest because bicyclic tetrahydrofurans are building blocks for the synthesis of a number of prostaglandins and prostacyclins. The cyclization is performed with bromine or iodine under kinetic conditions and the bicyclic products are obtained in good yield. The stereochemical outcome of this haloetherification reaction is determined by steric interactions and the formation of the exo-isomer is generally favored52-56. 

Haloetherification is closely related to halolactonization although it is used less often. Its main application is the diastereoselective synthesis of synthetically useful substituted tetrahy-drofurans. The mechanism of the asymmetry transfer of the reaction has been investigated using a transition-structure model based on AM1 calculations167. The strong correlation between model and experimental results makes the proposed rationale extremely attractive. 

Fujioka H, Kitagawa H, Nagatomi Y, Kita Y (1996) Asymmetric induction via an intramolecular haloetherification reaction of chiral ene acetals a novel approach to optically active... 

Hennecke developed enantioselective haloetherification reactions via desymmetrisation of in situ generated meso-iodonium intermediates (Scheme 2.37). Chiral sodium phosphate 58 was used for the cyclisation of symmetrical ene-diol substrates 59 with l-iodopyrrolidin-2-one (60), and the corresponding iodoetherification products 61 were obtained with up to 71% ee. 

Scheme 2.37 Enantioselective haloetherification of ene-diols with the use of chiral sodium(i) phosphate.

Intramolecular haloetherification of ene- and diene-acetals Asymmetric synthesis involving chiral oxonium ion intermediates 12SL825. lodination of aromatic and heteroaromatic compounds in water as an eco-friendly solvent 13COS265. 

While intermolecular haloetherification of alkenylboronie esters is of limited synthetic interest, due to the lack of regioselectivity and the concomitant loss of boron, the intramolecular version has opened a new route to tetrahydrofuran- and tetrahy-dropyran-substituted a-iodoboronic esters (Scheme 9.4) [15]. 

The 2-deoxy-2-fluoro-2-iodo-hexopyranoses 1 and 2 have been prepared from 2-fluoro-D-glucal (Scheme 1). Haloetherification of glycal 3 (NBS, ROH) gave the P-glycosides 4, which underwent radical cyclisation on abstraction of the bromine atom (see Chapter 14). Free radical bromination (NBS, CCI4, hv) of... 

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